Ondansetron, whose systematic chemical name is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, and whose molecular formula is
is the active ingredient of FDA approved antiemetic drugs that are indicated for treatment of nausea and vomiting associated with some cancer chemotherapy and radiotherapy and for the prevention of postoperative nausea and/or vomiting. Ondansetron is commercially available in orally disintegrating tablets and ondansetron hydrochloride dihydrate is commercially available in tablets and in oral solution, each under the brand name Zofran®.
Ondansetron has one chiral center. Ondansetron was first disclosed as a racemate in the patent literature in U.S. Pat. No. 4,695,578 (“the '578 patent”) in 1987. The '578 patent describes several ways by which ondansetron can be made. In Example 7 of the '578 patent, ondansetron was prepared by treating a 0.34 M solution of the hydrochloride salt of 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one of formula (IIa):
in water with 2.9 equivalents of 2-methylimidazole of formula (III):
The reaction was conducted at about 100° C. and required 20 hours to go to completion. Ondansetron was obtained in 82% yield after a single recrystallization. According to a general discussion of this reaction contained in the '578 patent, it may be carried out in a suitable solvent such as water or an alcohol, e.g. methanol, or mixtures thereof and at a temperature of from 20° to 150° C.
In Example 4 of the '578 patent, ondansetron was prepared by N-methylation of 1,2,3,9-Tetrahydro-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one of formula (IV):

A solution of the formula (IV) compound in dry N,N-dimethylformamide was added to a solution of sodium hydride in dry dimethylformamide to deprotonate the 1,2,3,9 tetrahydrocarbazol-4-one ring nitrogen and then the resulting anion was reacted with dimethylsulfate. The yield of the reaction was only about 21%. According to a general discussion of this reaction contained in the '578 patent, the reaction can be carried out in an inert organic solvent such as an amide, e.g. dimethylformamide; an ether, e.g. tetrahydrofuran; or an aromatic hydrocarbon, e.g. toluene.
Other preparations of ondansetron disclosed in the '578 patent include Example 8, where ondansetron was prepared by Michael-type addition of 2-methylimidazole to 9-methyl-3-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one of formula (V)
The reaction was conducted in refluxing water over a 20 hour period and occurred in 44% yield. According to a general discussion of this reaction in the '578 patent, suitable solvents include water; esters, e.g. ethyl acetate; ketones, e.g. acetone, or methylisobutylketone; amides, e.g. dimethylformamide; alcohols, e.g. ethanol; and ethers, e.g. dioxane or tetrahydrofuran; or mixtures thereof.
In Example 18(ii) of the '578 patent, ondansetron was prepared by substitution of 2-methyl-1H-imidazole for chloride in 3-(chloromethyl)-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one of formula (VI):

The reactants were stirred in dry DMF under nitrogen at 90° C. for 3.75 hours. The reaction occurred in about 72% yield. According to a general discussion of this reaction contained in the '578 patent, it can be carried out in an amide solvent, e.g. dimethylformamide; an alcohol, e.g. methanol or industrial methylated spirit; or a haloalkane, e.g. dichloromethane.
In Example 19 of the '578 patent, 2,3,4,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1H-carbazole maleate of formula (VII):
was oxidized by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in dry THF and the counterion was separated to give ondansetron in 55% yield.
In Example 20, DDQ was used to oxidize 2,3,4,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1H-carbazol-4-ol of formula (VIII):
in 41% % yield (the '578 patent actually reports a yield corresponding to a 413% theoretical yield. The most likely explanation for the error is omission of a decimal place after the decimal point of the mass yield. Thus, we infer that the actual yield was 41%). According to a general discussion in the '578 patent, the oxidation reactions of Examples 19 and 20 may be conducted in ketones, e.g. acetone or butanone; ethers e.g. tetrahydrofuran or dioxane; amides, e.g. dimethylformamide; alcohols, e.g. methanol; hydrocarbons, e.g. benzene or toluene; halogenated hydrocarbons, e.g. dichloromethane; and water or mixtures thereof.
U.S. Pat. No. 5,478,949 discloses a multistep process for preparing ondansetron that concludes with the step of N-alkylating the methylene group alpha to the oxo group of the 1,2,3,9 tetrahydrocarbazol-4-one ring system of the compound of formula (IX)
with 2-methylimidazole to give a compound of formula (X):
which is converted in situ to ondansetron by cleaving the oxalate group with a second nucleophile (EtO−) that also is present in the reaction mixture. The calculated theoretical yields ranged from 75% to 87.3%.
U.S. Pat. No. 6,388,091 discloses a process for preparing ondansetron wherein the silyl enol ether of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one of formula (XI):
is alkylated with a 1-(N,N-dialkylaminomethyl)-2-methylimidazole of formula (XII):
where substituent R is N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, morpholin-4-yl, piperidin-1-yl or pirrolidin-1-yl. According to the '091 patent, the reaction can be performed in an organic solvent such as methylene chloride, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, toluene, N,N-dimethylformamide, ethanol and a mixture thereof, or in a mixture of one of the above organic solvents and water to induce precipitation of the product. In the Examples, ondansetron was recovered in 81–86% yield.
U.S. Pat. No. 4,957,609 describes a process for preparing ondansetron and related compounds wherein the last step is closure of the central ring of the 1,2,3,9-tetrahydrocarbazol-4-one ring system starting with a compound of formula (XIII):
wherein X is a hydrogen or a halogen atom using a copper or palladium catalyst depending upon the identity of substituent X. When a palladium catalyst is used, suitable solvents include nitrites, e.g. acetonitrile, alcohols e.g. methanol or ethanol, amides, e.g. dimethylformamide, N-methylpyrrolidone or hexamethylphosphoramide, and water. When a copper catalyst is used, suitable solvents include amides, e.g. dimethylformamide, N-methylpyrrolidone or hexamethylphosphoramide, nitrites, e.g. acetonitrile, and alcohols, e.g. ethanol.
U.S. Pat. No. 4,739,072 describes another cyclization process for preparing ondansetron and related compounds. In this process, cyclization of the starting material, a hydrazine of formula (XIV),
is induced with an acid. The Lewis acid ZnCl2 was used in the examples. According to the '072 patent, the reaction can be performed in an aqueous medium, which may be aqueous alcohol (e.g. methanol, ethanol or isopropanol) or an aqueous ether (e.g. dioxane or tetrahydrofuran) as well as mixtures of such solvents. Anhydrous reaction media in which the cyclization can be conducted include one or more alcohols or ethers, carboxylic acids (e.g. acetic acid) or esters (e.g. ethyl acetate).
Chinese Patent Application No. 11143234 discloses additional one-step processes for preparing ondansetron which are related in that they install the (2-methyl imidazolyl)methylene group on the 1,2,3,9-tetrahydrocarbazol-4-one ring system.
It will be appreciated that considerable effort has been expended by synthetic chemists to discover a process for preparing ondansetron that represents an improvement over the processes described in the '578 patent. In fact, the preceding discussion of ondansetron preparation processes focuses on the final step of what, in many instances, are lengthy synthetic sequences from commercially available starting materials to ondansetron. The present invention arose out of our efforts to achieve improved results over those obtained in the '578 patent with a process that was well suited for scale up and industrial production of ondansetron without abandoning the basic synthetic strategies offered in the '578 patent. Accordingly, disclosed herein are improvements to the transamination process of compound (IIa) and related compounds that increase the reaction rate, yield and the general economic efficiency of producing ondansetron from such compounds.